4-3492937-ACCC-A

Variant names:

• chr4-3492937-ACCC-A
• rs794727884
• NM_173660.5:c.955_957delCCC

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_173660.5(DOK7):​c.955_957delCCC​(p.Pro319del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000359 in 1,392,408 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P319P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DOK7 NM_173660.5 conservative_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19
• Publications: 2 publications found

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_173660.5. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.955_957delCCC	p.Pro319del	conservative_inframe_deletion	Exon 7 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.955_957delCCC	p.Pro319del	conservative_inframe_deletion	Exon 7 of 10	NP_001288000.1
	DOK7	NM_001363811.2		c.523_525delCCC	p.Pro175del	conservative_inframe_deletion	Exon 5 of 8	NP_001350740.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.955_957delCCC	p.Pro319del	conservative_inframe_deletion	Exon 7 of 7	ENSP00000344432.5
	DOK7	ENST00000643608.1		c.523_525delCCC	p.Pro175del	conservative_inframe_deletion	Exon 5 of 8	ENSP00000495701.1
	DOK7	ENST00000515886.5	TSL:2	c.25_27delCCC	p.Pro9del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000725 AC: 1 AN: 138024 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1392408 Hom.: 0 AF XY: 0.00000436 AC XY: 3 AN XY: 687360

African (AFR) AF: 0.00 AC: 0 AN: 31644

American (AMR) AF: 0.00 AC: 0 AN: 35850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.00 AC: 0 AN: 35760

South Asian (SAS) AF: 0.00 AC: 0 AN: 79472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5162

European-Non Finnish (NFE) AF: 0.00000462 AC: 5 AN: 1081210

Other (OTH) AF: 0.00 AC: 0 AN: 57982

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000509 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794727884; hg19: chr4-3494664;